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CC2D1A Regulates Human Intellectual and Social Function As Well As NF-Κb Signaling Homeostasis

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CC2D1A Regulates Human Intellectual and Social Function As Well As NF-Κb Signaling Homeostasis CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Manzini, M. C., L. Xiong, R. Shaheen, D. E. Tambunan, S. Di Costanzo, V. Mitisalis, D. J. Tischfield, et al. 2015. “CC2D1A Regulates Human Intellectual and Social Function as well as NF- κB Signaling Homeostasis.” Cell reports 8 (3): 647-655. doi:10.1016/ j.celrep.2014.06.039. http://dx.doi.org/10.1016/j.celrep.2014.06.039. Published Version doi:10.1016/j.celrep.2014.06.039 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065436 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Cell Rep. Author manuscript; available in PMC 2015 February 19. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Cell Rep. 2014 August 7; 8(3): 647–655. doi:10.1016/j.celrep.2014.06.039. CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis M. Chiara Manzini1,2,3,12, Lan Xiong4,5, Ranad Shaheen6, Dimira E. Tambunan1,2,3, Stefania Di Costanzo1,2,3,12, Vanessa Mitisalis1,2,3, David J. Tischfield1,2,3, Antonella Cinquino1,2,3, Mohammed Ghaziuddin7, Mehtab Christian5, Qin Jiang4, Sandra Laurent5, Zohair A. Nanjiani8, Saima Rasheed9, R. Sean Hill1,2,3, Sofia B. Lizarraga1,2,3,13, Danielle Gleason1,2,3, Diya Sabbagh1,2,3,6, Mustafa A. Salih10,14,*, Fowzan S. Alkuraya6,14,*, and Christopher A. Walsh1,2,3,11,14,* 1Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115, USA 2Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA 3Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA 4Department of Psychiatry, Research Centre of Montreal Mental Health University Institute, University of Montreal, Montreal, QC H1N 3V2, Canada 5University of Montreal Hospital Research Centre, Montreal, QC H2L 2W5, Canada 6Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia 7Department of Child and Adolescent Psychiatry, University of Michigan Health System, Ann Arbor, MI 48109, USA 8Ma Ayesha Memorial Centre, University of Karachi, Karachi 75350, Pakistan 9Autism Institute, Karachi 74000, Pakistan 10Division of Pediatric Neurology, Department of Pediatrics, King Saud University College of Medicine, Riyadh 11461, Saudi Arabia 11Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). *Correspondence: [email protected] (M.A.S.), [email protected] (F.S.A.), [email protected] (C.A.W.). 12Present address: Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA 13Present address: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA 14Co-senior author SUPPLEMENTAL INFORMATION Supplemental Information includes Supplemental Experimental Procedures, four figures, and one table and can be found with this article online at http://dx.doi.org/10.1016/j.celrep.2014.06.039. AUTHOR CONTRIBUTIONS M.C.M., L.X., M.A.S., F.S.A., and C.A.W. designed the study. M.C.M., L.X., R.S., Q.J., S.L., R.S.H., S.B.L., D.E.T., S.D.C., V.M., D.J.T., A.C., D.G., and D.S. designed and performed experiments and analyzed data. M.G., M.C., Z.A.N., S.R., M.A.S., and F.S.A. examined patients and provided materials. M.C.M., M.A.S., F.S.A., and C.A.W. wrote the manuscript. Manzini et al. Page 2 SUMMARY Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intra-cellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients. INTRODUCTION Autism spectrum disorder (ASD) is a highly heritable neuropsychiatric condition, but its genetic architecture remains unclear. Although common genetic variants have been shown to confer risk for this disorder (Cross-Disorder Group of the Psychiatric Genomics Consortium et al., 2013), ASD is also caused by rare mutations of large effect, suggesting a genetic architecture partially similar to intellectual disability (ID) (Devlin and Scherer, 2012). Because ASD is comorbid with ID in 30%–50% of cases (Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014), these disorders may not be genetically distinct. However, it is not clear how mutations in the same gene can have divergent consequences, ranging from severe ID to prominent social defects with preserved intellectual function. Here, we report that null mutations in coiled-coil and C2 domain containing 1A (CC2D1A) consistently cause a variable spectrum of presentations including ID, ASD, and seizures even within the same family. CC2D1A encodes a multifunctional signaling scaffold that regulates multiple pathways involved in neuronal differentiation by linking transmembrane receptors and their downstream effectors, including protein kinase B (PKB/AKT) activators (Nakamura et al., 2008), and multiple effectors upstream of activation of the transcription factor nuclear factor κB (NF-κB) (Chang et al., 2011; Zhao et al., 2010). We performed both gain- and loss-of-function experiments to define the role of Cc2d1a in neuronal differentiation and intracellular trafficking. Cc2d1a depletion in murine neurons leads to a striking reduction in dendritic complexity and dendritic spine number. By exploring the involvement of Cc2d1a in a variety of signaling pathways, we discovered that the NF-κB pathway was most strongly affected. Cc2d1a loss and gain of function both activated NF-κB in developing neurons, and restoring NF-κB activity during differentiation rescued dendritic complexity in Cc2d1a knockdown neurons. Our results suggest an important role of Cc2d1a in regulating NF-κB activity during brain development and that NF-κB activation may underlie some of the defects caused by Cc2d1a loss of function. Cell Rep. Author manuscript; available in PMC 2015 February 19. Manzini et al. Page 3 RESULTS AND DISCUSSION NIH-PA Author ManuscriptNull NIH-PA Author Manuscript Mutations in NIH-PA Author Manuscript CC2D1A Cause ASD, ID, and Seizures We report 4 families with a total of 16 individuals affected by a spectrum of cognitive and social impairments, including ASD, nonsyndromic ID (NSID), and seizures (Figure 1A). Families 1 and 2 represent two related consanguineous families from Saudi Arabia. In family 1, one male is affected by ASD and ID (individual 1:4), one male by cognitive problems and aggressive behavior (1:1), and two females by moderate-to-severe NSID (1:2 and 1:3). In family 2, two males (2:1 and 2:2) and one female (2:3) are affected by combinations of ASD, severe NSID, language impairment, and seizures (Table S1 for clinical information). The parents in family 3 are first cousins once removed, also from Saudi Arabia, and four siblings (three males and one female) are affected by severe NSID with language impairment (Table S1). Finally, five Pakistani males with variable presentation belonged to family 4: individuals 4:1, 4:2, and 4:4 had moderate NSID, individual 4:3 was more severely affected with language impairment and borderline autistic features, and individual 4:5 had moderate ASD/ID (Table S1). The parents reported being unrelated. Genomic DNA from all family members was run on genome-wide SNP arrays, and genotyping data were analyzed under an autosomal recessive model. Linkage analysis was performed independently on the first three families, but all studies identified a common region on chromosome 19p13 with a LOD score of 3.4 for families 1 and 2 and of 3.8 for family 3. The locus had been previously linked to NSID in Israeli-Arab families, who carried a 3,589 bp deletion in CC2D1A generating an 85 kDa protein fragment (Basel- Vanagaite et al., 2006) making CC2D1A a strong positional candidate gene. The Saudi families did not carry the Israeli-Arab deletion (data not shown), but upon Sanger sequencing of CC2D1A, we identified a homozygous G > T transversion at the exon-intron junction of exon 6 (c.748+1 G > T), which segregated with the disease in the families (Figure 1B). The shared SNP haplotype observed in all affected individuals indicated that c. 748+1 G > T is a founder mutation in the Saudi population shared by all three families and inherited from a distant common ancestor (Figure S1). A common region of homozygosity including CC2D1A was also identified in all affected individuals in family 4. Exome sequencing identified a 1 bp deletion in exon 3 (c.346 delA) leading to an early frameshift (p.Lys116Argfs*81) (Figure 1B).
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